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Selectively bred rat lines, developed to model genetic contributions to alcohol abuse, include the Indiana alcohol-preferring (P) and alcohol-nonpreferring (NP) lines, and the Alko-Alcohol (AA) and Alko-Nonalcohol (ANA) lines. Preferring and nonpreferring lines were compared in their response to intraperitoneal injection of either ethanol or isotonic saline using c-Fos expression as a marker of neuronal activity. Although line differences were noted in several brain regions, the principal finding was that alcohol-nonpreferring lines (NP and ANA) displayed greater c-Fos expression in the locus coeruleus (LC) relative to the alcohol-preferring lines (P and AA) following injection of 3.0 g ethanol/kg. These data point to the LC as an area which may play a role in the differences in voluntary ethanol consumption between rat lines genetically bred for low and high ethanol preference.

To examine the development of strain differences in the response of the chorda tympani nerve (CT) to NaCl, integrated CT responses to NaCl were recorded from Wistar and F344 rats between 15 and 36 days old. NaCl responses before and after the application of amiloride were expressed relative to 0.5 M NH4Cl as a standard. At 15-17 days old, there were no significant strain differences in the magnitude of NaCl responses. Strain differences emerged at 21-23 days old with responses of F344 rats significantly higher than those of Wistars; these differences became more pronounced at 34-36 days old. Amiloride significantly reduced responses to NaCl at all ages and eliminated any differences between the strains. Changes in neural responsiveness correspond with the emergence of the behavioral expression of F344 salt aversion.

Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.

Background: Experience with human seminal plasma hypersensitivity in the last decade has led to increased physician awareness of symptoms consistent with human seminal plasma sensitization in women. Incidence and prevalence of human seminal plasma hypersensitivity in women are unknown., Objective: A questionnaire survey was distributed to determine the prevalence of human seminal plasma hypersensitivity among a population of women suspected of having this disorder., Methods: A questionnaire designed to elicit age, symptoms, duration of symptoms, number of sexual partners, time to onset of symptoms after first human seminal plasma exposure, onset of symptoms after first intercourse, recent gynecologic procedures, history of atopy, vaginitis, food or drug allergy and family history of atopy was distributed to 1,073 women who suspected they had symptoms consistent with human seminal plasma hypersensitivity. Women were considered "possible" for human seminal plasma hypersensitivity if they reported two or more symptoms consistent with localized or systemic human seminal plasma hypersensitivity. Women were considered "probable" for disease if they fulfilled the "ultimate criterion" defined as complete prevention of symptoms with a condom. Women with "possible" localized or systemic human seminal plasma hypersensitivity who had persistent symptoms despite use of a condom served as cohort control groups., Results: Two-hundred sixty-six women reported symptoms "possible" for human seminal plasma hypersensitivity (88 localized and 178 systemic). When the "ultimate criterion" was applied, 130 (46 localized and 84 systemic) of the 266 women were identified as having "probable" human seminal plasma hypersensitivity. The responses to most of the questions from each group were very similar. A significantly shorter time interval to symptom onset after initial human seminal plasma exposure was more common for women with "probable" localized human seminal plasma hypersensitivity compared with their cohort control group (49 months versus 108 months; P < .02) whereas a significantly increased number of women with "probable" systemic human seminal hypersensitivity gave positive food allergy histories compared with their cohort control group (31 versus 20; P < .05). Atopy did not appear to be a risk factor for human seminal plasma hypersensitivity., Conclusions: Evaluation of women with symptoms suggestive of human seminal plasma hypersensitivity using a validated questionnaire indicates that this disorder is more common than previously recognized.

The induction of c-Fos-like immunoreactivity (c-FLI) in the intermediate division of the nucleus of the solitary tract (iNTS) has been shown to be a reliable cellular correlate of the acquisition and/or behavioral expression of a conditioned taste aversion (CTA). To begin to define neuroanatomical structures and pathways that contribute to this cellular response and to CTA learning in general, electrolytic lesions of the amygdala were combined with immunostaining for c-FLI. Rats were given either unilateral or bilateral electrolytic lesions of the amygdala or "sham' operations. Following surgery "paired' animals were given a single conditioning trial consisting of intraoral infusion of 5 ml 0.15% sodium-saccharin followed by injection with LiCl (0.15 M, 20 ml/kg, i.p.) while "unpaired' controls received a non-contingent saccharin-LiCl presentation. When tested, unilateral-lesioned rats displayed a CTA by rejecting the saccharin, but increases in c-FLI were evident only on the side of the iNTS contralateral to the lesion. Rats with bilateral lesions showed no evidence of having acquired a CTA and no increase in c-FLI in iNTS relative to unpaired controls. These findings support involvement of amygdala in CTA learning and suggest that a lateralized connection between amygdala and iNTS is necessary for the conditioned c-FLI which is induced by exposure to a conditioned aversive taste.

Recently, glucagon-like peptide-1-(7-36) amide (GLP-1) and leptin have been implicated in the regulation of food intake. In the present study, we compared the effects of third ventricular administration (i3vt) of leptin (3.5 micrograms) and GLP-1 (10.0 micrograms) on short-term food intake and c-Fos-like immunoreactivity (c-FLI) in hypothalamic, limbic, and hindbrain areas in the rat. Relative to controls, infusion of leptin or GLP-1 (3 h before lights off) significantly reduced food intake over the first 2 h in the dark phase (53 and 63%, respectively). In different rats, infusion of leptin or GLP-1 elevated c-FLI in the paraventricular hypothalamus and central amygdala. Furthermore, leptin selectively elevated c-FLI in the dorsomedial hypothalamus, whereas GLP-1 selectively elevated c-FLI in the nucleus of the solitary tract, area postrema, lateral parabrachial nucleus, and arcuate hypothalamic nucleus. The fact that most of the c-FLI after leptin or GLP-1 administration was observed in separate regions within the central nervous system (CNS) suggests different roles for leptin and GLP-1 in the CNS regulation of food intake and body weight.

When consumption of a novel taste (conditioned stimulus; CS) is followed by exposure to a toxin, organisms will avoid consumption of that taste in the future. This learned response, known as a conditioned taste aversion (CTA), can be demonstrated using a variety of drugs, including lithium chloride (LiCl) and ethanol. c-Fos immunohistochemistry was used to examine neural activation in the rat brainstem associated with drug administration and with a CS taste previously paired with these drugs. Relative to saline controls, animals injected with either LiCl (76 mg/kg) or ethanol (3.5 g/kg) displayed greater c-Fos expression in area postrema, nucleus of the solitary tract (NTS), and lateral parabrachial nucleus. At these doses, LiCl- and ethanol-injected groups did not differ from each other. For establishing a CTA, intraoral infusion of a 0.15% saccharin solution was followed by injection of either LiCl or ethanol. Both LiCl and ethanol produced quantitatively similar CTAs. Relative to unpaired control groups, saccharin paired with either drug induced significant c-Fos expression in NTS. Thus, like LiCl, ethanol and tastes that have become aversive by virtue of their association with ethanol activate brainstem regions hypothesized to play a role in CTA learning.

Conditioned taste aversion (CTA) learning is a robust form of classical conditioning in which animals rapidly associate a flavor with aversive internal symptoms. The present study assessed CTA learning in transgenic mice deficient in a specific nonreceptor tyrosine kinase (the fyn mutant). Fyn mutants show impaired long-term potentiation and marked deficits in acquisition of spatial learning tasks. To assess whether they are also impaired in CTA learning, fyn mutant and wild-type mice received 2 conditioning trials consisting of access to a flavored solution followed by administration of LiCl. Fyn mutant mice acquired significant CTAs following a single conditioning trial and these aversions were comparable to those seen in wild-type mice. These results indicate that the fyn mutation does not interfere with the acquisition of CTAs and hence that this mutation is not associated with a global learning deficit.

Background: Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma., Objectives: The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma., Methods: Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiring > or = 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was "therapeutic success" or reduction of daily corticosteroid use by 50% or more., Results: The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) (p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline (p < 0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (> or = 50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) (p < 0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group (p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group., Conclusions: Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma.

Sodium depletion in the neurologically intact rat (Intact) produces a prompt and robust intake of NaCl. After chorda tympani nerve transection (CTX), there is a longer latency and a reduced intake of NaCl. The CTX rat depends on remaining gustatory and postingestive information to direct NaCl intake. In the present study, the effect of the removal of the postingestive signals of ingested NaCl (by means of a chronic gastric fistula) on the NaCl intakes and licking patterns of Intact and CTX rats was studied. When the gastric fistula was open (Sham), ingested NaCl did not pass beyond the stomach, thus negative postingestive stimulation was absent. After overnight sodium depletion, when postingestive stimulation was present (i.e., gastric fistula closed; Real), the CTX group drank significantly less 0.3 M NaCl than the Intact group over the 2-h test [11.7 +/- 1.6 (CTX) vs. 15.3 +/- 2.8 (Intact) ml]. In contrast, when postingestive signals were absent (i.e., Sham) the Intact group ingested 52.5 +/- 4.4 ml, whereas the CTX group had ingested only 12.4 +/- 3.1 ml of 0.3 M NaCl. Lickometer data analysis revealed that even during the first minute of the test the CTX/Real group generated significantly fewer licks than any of the other groups. Thus, although the CTX group was sensitive to inhibitory postingestive signals in the early portion of the appetite test, the absence of these signals did not release the robust and sustained intake of NaCl characteristic of the Intact group. These results suggest that information provided by the chorda tympani nerve is critically important to the strong motivational properties of NaCl after sodium depletion.

Fischer 344 (F344) rats fail to prefer sodium chloride (NaCl) solution to water, and this behavior is dramatically altered by bilateral transection of the chorda tympani nerve (CTX). Tests of retention and generalization of a conditioned taste aversion (CTA) to 0.15 M NaCl were used to assess alterations in salt taste perception after CTX. A CTA was established to 0.15 M NaCl in groups of F344 and Wistar rats after two pairings with LiCl (IP, 2% body weight; 0.15 M). After conditioning, animals received bilateral CTX or sham operations. Approximately 2 weeks after surgery animals were tested for retention of the CTA. Aversion to 0.15 M NaCl was evident in CTX and SHAM rats that had been conditioned prior to surgery, with no apparent difference in magnitude as a function of surgical condition. Thus, although CTX profoundly alters F344 rats' hedonic response to NaCl, it does not alter perceptual characteristics so markedly that NaCl is no longer recognized as the stimulus presented during aversion conditioning. Rather these studies suggest that in both the F344 and Wistar strains the chorda tympani nerve is not necessary for retention of a presurgical CTA to NaCl. These studies, therefore, do not provide evidence of changes in NaCl perceptual "quality" as a consequence of CTX either in F344 rats, where such changes were indicated by the preference data, or in the Wistar rat, where they were not.

The immature gustatory system of the neonatal rat is characterized by sensitivity to disruption by early interventions such as receptor or nerve damage. The present studies examined the effect of chorda tympani transection (neoCTX) of neonates on adult preference for salt and nonsalt stimuli. NeoCTX at 10 days of age led to a striking change in adult rats' preference for NH4Cl solutions but little change in preference for other solutions, including NaCl and KCl. Permanent anatomical effects of neoCTX included failure of the nerve to regenerate and a loss of all fungiform taste buds. Preference for NH4Cl was not due to an inability to discriminate it from NaCl. Following taste aversion conditioning to NaCl, neoCTX rats clearly distinguished between NaCl and NH4Cl. The effects on NH4Cl preference reflect a sensitive period during development because adult rats receiving similar surgery did not show any change in NH4Cl preference.

Tumors often cause declines in food intake and body weight, a condition referred to as tumor anorexia. A macrophage-derived peptide known as tumor necrosis factor (TNF) has been proposed as an important mediator of cancer anorexia and cachexia. Our work with an animal model of this condition indicates that strong learned aversions to the available diet arise in rats bearing implanted tumors and that these aversions contribute significantly to depressions in food intake and body weight. Lesions of the area postrema and nearby caudal medial nucleus of the solitary tract (APcmNTS) markedly attenuate both the learned aversions and the anorexia induced by tumor growth. A strikingly similar pattern of effects on tumor-induced aversions and anorexia was seen after subdiaphragmatic vagotomy and after capsaicin treatments. The similarity in the effects of all three treatments suggest that they involve interruption of the same system, presumably afferent signals conveyed by the vagus nerve to the nucleus of the solitary tract. The extent to which peripheral TNF administration generates symptoms similar to those produced by tumor growth was also examined. TNF administration was associated with the development of strong aversions to a novel but not a familiar diet. Area postrema lesions were found to significantly attenuate the effects of TNF on novel diet intake and preference. These observations provide parallels between the effects of TNF and the effects of tumor growth on diet aversions and food intake.

These studies examined the relationship between salt preference of adult offspring and their mothers' symptoms of morning sickness during pregnancy. College students who could provide information about their mothers' symptoms of morning sickness completed a survey about their dietary salt intake (study 1; n = 169) or rated and consumed ten snack foods (study 2; n = 66). In study 1 a salt-use score was calculated based on responses to the Salt Intake Questionnaire; offspring of women with moderate or severe vomiting reported a significantly higher level of salt use (p < 0.01) than those whose mothers report little or no symptoms. In study 2 saltiness and pleasantness ratings of high-salt foods, intake of those foods and total sodium intake were the focus of analysis. Offspring of women reporting moderate or severe vomiting showed a significantly greater preference for the snack food subjects rated as saltiest than those whose mothers reported no or mild vomiting. They also ate more of that food and consumed more total sodium during the test session. Effects were stronger in Caucasian than Asian subjects. These studies suggest that moderate to severe vomiting during pregnancy can be associated with significantly higher salt intake in offspring. Thus, a gestational event may be an important determinant of salt intake and preference in adulthood.

Six auto parts manufacturing workers were referred for evaluation of a 6-week history of work-related dyspnea, cough, and fatigue. Two workers also reported fever and weight loss. All six worked in a machining area where a waterbased metalworking fluid was used and recirculated under high pressure, thereby creating an aerosol. Chest radiographs revealed pulmonary interstitial infiltrates in four workers. Lung function tests showed that four workers had decreased diffusing capacity. After removal from the work area, all workers recovered. The metalworking fluid was cultured for bacteria and fungi. Isolates from broth cultures were sonicated to obtain antigen extracts. Serum precipitins to one or more of the microbial isolates were identified in all six workers but not in eight of nine nonexposed control subjects. The most frequent precipitin response (six of six workers) was against antigens of Pseudomonas fluorescens, which was cultured from the metalworking fluid. In all workers, precipitins to at least one other cultured organism were detected; these included Aspergillus niger, Staphylococcus capitas, an acid-fast Rhodococcus sp, and Bacillus pumilus. This represents the first report of hypersensitivity pneumonitis associated with industrial exposure to aerosolized metalworking fluid. Observed precipitin responses to a variety of microbial contaminants in metalworking fluid strongly suggest a causative role for microbial antigens in the induction and elicitation of this manifestation of hypersensitivity pneumonitis.

Temporal parameters of taste aversion learning are known to differ markedly from other learning paradigms in that acquisition occurs despite lengthy delays between exposure to conditioned (CS) and unconditioned stimulus (US). Far less consideration has been paid to very brief CS-US intervals and the possibility that this learning may also be distinguished by an ineffectiveness of close temporal contiguity between CS and US. The effectiveness of a very brief CS-US interval (10 s) was compared with that of 2 lengthier intervals (15 and 30 min). Temporal control of CS delivery (0.15% saccharin solution) into the oral cavity and US delivery (7.5 mg/kg apomorphine hydrochloride) into circulation involved infusion pumps and indwelling catheters. Using a 1-trial learning paradigm, CS-US delays of 15 and 30 min led to significant aversions whereas the 10-s CS-US interval did not, suggesting that close temporal contiguity between CS and US is neither necessary nor sufficient for conditioned taste aversion acquisition.

Amphetamine and lithium chloride (LiCl) are both effective unconditioned stimuli (USs) in the establishment of conditioned taste aversions (CTA) in the rat. However, the mechanism of action of these drugs is quite different with the area postrema and related emetic circuitry critical to the response to LiCl but not amphetamine. c-Fos immunohistochemistry was used to define brain regions activated during drug administration and during expression of a CTA using either amphetamine or LiCl as the US drug. Administration of LiCl induced dense c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) while amphetamine induced only light staining in this area. A conditioned stimulus (CS) saccharin solution paired with amphetamine, however, was associated with c-FLI in NTS in a pattern quite similar to that seen to a LiCl-paired CS. This suggests that the pattern of c-Fos expression to a taste CS after conditioning is characteristic of aversion conditioning, in general, and appears not to represent a matching of the conditioned response to specific unconditioned effects of the drug. To examine this conditioned response further, c-FLI to the aversive saccharin CS was compared to the response to quinine hydrochloride, which is innately aversive. Although behaviorally the animals' ingestive responses were quite similar, the saccharin CS induced significant elevations of c-FLI in NTS whereas the quinine did not. Thus, a taste which had become aversive by virtue of conditioning induced c-FLI expression in NTS while a taste which was inherently aversive did not.

Background: We performed a cost-benefit analysis of a previously described self-management program for adult asthma., Methods: Direct and indirect cost data from 47 subjects who participated in the self-management program were analyzed. In particular, costs incurred by the subjects 1 year before participation were compared with costs incurred 1 year after participation., Results: The cost-benefit analysis indicated that the program was beneficial, reducing the cost of asthma to each patient by $475.29. The benefit came primarily from reductions in hospital admissions (reduced from $18,488 to $1538) and income lost as a result of asthma (reduced from $11,593 to $4589). The asthma self-management program cost $208.33 per patient. Comparison of the program cost with the program benefit produced a 1:2.28 cost-benefit ratio, demonstrating that the program more than paid for itself., Conclusion: A self-management program for adult asthma effectively reduced the cost associated with asthma. The findings are especially salient because the subjects' asthma was generally under good medical control when they participated in the program. The savings were therefore not the result of improved medical treatment; medical treatment was a controlled parameter, not a variable, in the self-management study. The self-management program for adult asthma was cost-beneficial.

Background: We developed and evaluated a self-management program for adult asthma. In developing the program, we considered questions of format and behavior control. The format we selected included components known to be effective in educational settings. We regulated asthma management behavior through the introduction of environmental cues., Methods: Seventy-six subjects, whose asthma was generally under medical control, were assigned randomly to either a treatment group or a waiting-list control group. Those in the treatment group were exposed to a 7-week program that incorporated proven features of providing effective training and establishing behavioral control. Subsequently, subjects in the control group received the treatment. Short-term evaluation of the treatment was made after the subjects in the experimental group were trained but before the control subjects were trained. Long-term evaluation was conducted after both groups of subjects were trained., Results: Over the short term, self-management training led to fewer asthma symptoms and physician visits and improvement in asthma management skills and cognitive abilities. Over the long term, self-management training was related to lower asthma attack frequency, reduced medication use, improvement in cognitive measures, and increased use of self-management skills., Conclusions: The program improved asthma management in patients whose conditions were already under good medical control. The effects of the program were apparent a year after the conclusion of self-management training.

Background: Rapid venom immunotherapy regimens have been developed to provide safe protection to individuals who have experienced Hymenoptera anaphylaxis by administering greater than 50 micrograms of venom over two to three hours on treatment day 1. A rapid venom immunotherapy protocol which consisted of administration of a cumulative dose of 58.55 micrograms of each venom on treatment day 1 followed by an accelerated build-up over 3 weeks to a final maintenance dose of 100 micrograms per venom was developed by our group in 1984., Objective: We report our 10-year cumulative experience with this rapid venom immunotherapy regimen., Methods: Seventy-seven venom-allergic patients received a cumulative dose of 58.55 micrograms per venom on treatment day 1 in an ambulatory care setting. Rapid venom immunotherapy was assessed for safety. A cost analysis was performed to compare rapid venom immunotherapy to a modified rush immunotherapy regimen., Results: Four patients (5.2%), experienced mild systemic reactions consisting of diffuse urticaria on day 1. Treatment was otherwise well tolerated. Resting events occurred in 21 patients, a mean number of 12 months (range: 3 days to 48 months) after treatment, without systemic reactions., Conclusions: This experience confirms that rapid venom immunotherapy is safe to administer in an ambulatory setting and should be considered especially for patients during the stinging insect season when rapid protection is required.

Amiloride-sensitive sodium channels in taste buds appear to play a key role in the response to NaCl stimulation, at least in adult rats. The researchers examined whether neonatal rats, which display an exaggerated preference for hypertonic NaCl solutions, lack functional amiloride-sensitive sodium channels. NaCl intake was significantly reduced by amiloride pretreatment, but water and ammonium chloride, NH4Cl, were unaffected. The researchers assessed whether the early appearance of amiloride sensitivity was mediated by effects on chorda tympani (CT) activity by sectioning the CT before testing. CT transection reduced intake of NaCl solutions and eliminated evidence of amiloride sensitivity. Amiloride sensitivity was also assessed by recording of whole-nerve CT activity at 8-11 days of age; the response to NaCl stimulation was significantly suppressed by amiloride. These data indicate that amiloride-sensitive sodium channels develop earlier than previously believed.

Human expression of pulmonary disease after exposure to chemicals is highly dependent on the locale and circumstances of the exposure. Most of the information about environmental hazards that is currently available has been obtained from epidemiological investigations. Chemical agents in the workplace have received considerable attention because the workplace is an ideal mini-epidemiological model of air pollution. Many instances of pulmonary immunotoxicology are engendered by adverse reactions to drugs but of necessity these can only be studied on a case-by-case basis. Although the overall expression of pathological processes in the anatomical structures of the respiratory system is limited, many of the clinicopathological features induced by chemicals present with features that are characteristic enough to suggest that several stimulus-response paradigms may be applicable. In this review the immunotoxicological impact of chemicals on the major anatomical components of the lung (the conducting airways, the alveolar, interstitial and capillary compartments, the pleura and the pulmonary vasculature) is considered. The two major classes of hypersensitivity induced in humans by chemicals are those involving IgE humoral and cell-mediated immune responses. Although other isotypic antibodies (IgM, IgG, IgA), as well as complement activation, have been demonstrated after specific types of exposure, the role of these immune components in the pathogenesis of disease does not appear to be of major importance. Chemicals with a special propensity for IgE sensitization and effects on the airways include polyisocyanates, acid anhydrides and platinum salts. Conditions that involve the lung parenchyma are exemplified by hypersensitivity pneumonitis, drug-induced pneumonia and berylliosis.

We observed that a group of detergent enzyme workers with known exposure to the subtilisin enzyme, Alcalase (Novo Industries, Bagsvaerde, Denmark), exhibited percutaneous sensitivity to Savinase (Novo Industries), a microbial protease, to which there was no previous occupational exposure. This was attributed to either cross-reactivity between these enzymes or to foreign enzyme contaminants contained in the Savinase antigen. The aims of this study were to determine the range of concentrations eliciting percutaneous responses to Alcalase and to another enzyme, Rapidase (an alpha-amylase) (Gist Brocades, Belgie, Netherlands); to compare the sensitivity of RAST and skin prick testing; and to characterize the relationship between wheal size and antigen concentration. Prick testing was conducted over six log10 antigen dilutions of Alcalase and Rapidase in 30 workers with previous exposure and skin reactivity to enzymes (group 1) and compared to nonexposed control groups, which included 60 atopic subjects (group 2) and 30 nonatopic subjects (group 3). The RAST was performed with Alcalase and Rapidase antigens. The percutaneous threshold concentrations in group 1 subjects varied widely from 10(3) to 10(-3) micrograms of protein per milliliter. Of 19 group 1 workers with skin test reactivity to Alcalase, 84% had positive RAST results; 83% of 24 workers who were reactive to Rapidase had positive RAST results. It was concluded that skin prick testing is preferred over in vitro methods for longitudinal monitoring of human sensitization to workplace allergens. In addition, the data predicted that based on a known Alcalase level of 0.07% in Savinase, 26% of Alcalase-sensitized subjects could react to Savinase. An excellent correlation (r > 0.97) was found between log concentration of antigen and wheal size parameters, with the log diameter and log area performing equally as well (r > 0.98). Analysis of variance revealed that more than 60% of intragroup variation represented human variability in wheal parameters at each concentration tested, whereas at least 95% of intergroup variation was due to regression. The excellent correlations of both wheal diameter and area with antigen concentrations were attributed to the very small changes observed between test concentrations.

The quaternary amine, benzalkonium chloride, has been associated with cutaneous and mucosal delayed hypersensitivity reactions and with paradoxical bronchoconstriction after use of aerosolized asthma medications. Until now, quaternary amines have not been reported to cause occupational asthma. We describe a case of occupational asthma caused by prolonged exposure to a cleaning solution containing benzalkonium chloride in the workplace. Single-blind, placebo-controlled, open-room challenges were performed to determine the specific agent responsible for the patient's symptoms. Pulmonary function and epicutaneous challenge tests were also performed. The patient had positive responses to challenges with a liquid toilet bowl cleaner containing benzalkonium chloride but was unreactive to other agents tested. Removal from the workplace resulted in complete resolution of symptoms. The exact mechanisms responsible for occupational asthma induced by quaternary amines remain unknown; however, this case emphasizes the importance of recognizing reactive chemicals as possible causes.

Taste aversion conditioning is characterized by its prompt acquisition despite the introduction of long delays between CS (taste) and UCS (toxic drug). Although the dramatic changes in behavioral response to a taste after this conditioning are well documented, relatively little is known about the changes in neural activity that accompany this learning. c-Fos immunohistochemical staining was employed to define brain regions activated during the expression of a conditioned taste aversion (CTA). The present studies examined c-Fos immunoreactivity in the brains of rats after i.p. injection of LiCl or NaCl or after intraoral infusion of a saccharin CS. LiCl administration, a common unconditioned stimulus (UCS) in CTA experiments, was found to induce c-Fos protein in a number of brainstem regions, including the nucleus of the solitary tract (NTS), medial and lateral pontine parabrachial nucleus (PBN), and hypoglossal nucleus. Conditioned animals received a single pairing of the CS saccharin with the UCS LiCl, while controls were exposed to the CS saccharin but received non-contingent LiCl 24 h after saccharin exposure. Following saccharin re-exposure, conditioned animals showed patterns of neuronal activation to a taste which were similar to those activated by the UCS drug. Specifically, the pattern of c-Fos expression in conditioned animals was confined to the same region of the NTS which showed the most activation following the UCS LiCl. This pattern of activation was not evident in controls re-exposed to saccharin.(ABSTRACT TRUNCATED AT 250 WORDS)

The chorda tympani nerve (CT) appears to be particularly responsive to NaCl stimulation of the tongue. However, in most strains of rat, bilateral transection of the CT (CTX) results in little alteration of salt preference. The Fischer 344 (F344) strain of rat is unusual in its lack of preference for any concentration of salt. We recently reported a dramatic change from aversion to preference for salt in F344 rats after CTX. The present studies further explored this alteration in salt preference of F344 rats with an expanded range of NaCl concentrations. Additionally, the specificity of the CT in mediating F344 salt aversion was examined by testing NaCl preference after glossopharyngeal nerve (GL) transections, combined CT and GL deafferentation, and partial desalivation. Comparison with Wistar rats revealed that salt preference of F344 CTX rats followed a typical preference/aversion pattern across a range of NaCl concentrations. Studies of GL section, either alone or combined with CT sectioning, indicated that F344 rats' aversion was dependent on the integrity of the CT and not the GL. Removal of sublingual and submaxillary salivary glands did not lead to preference changes similar to those after CTX, indicating that the effects of CTX are not secondary to desalivation. Overall, the findings point to signals from the CT as playing a primary role in the NaCl aversion displayed by the intact F344 rat.

Background: Localized vaginal inflammation after contact with seminal plasma has been previously described but without a clear understanding of the underlying immunopathogenesis. The purpose of this report is to describe three women who presented with localized postcoital vaginal reactions that were successfully treated with rapid immunotherapy using human seminal plasma proteins., Cases: One atopic and two nonatopic women with histories of immediate onset of localized postcoital vaginal symptoms and immediate skin test reactions to human seminal plasma were treated with rapid immunotherapy using their spouse's purified seminal plasma protein fractions. One of the women had decreased cutaneous reactivity post-therapy and detectable circulating specific immunoglobulin (Ig) G and IgE antibodies to her spouse's fractionated seminal plasma proteins. Increased IgG, IgE, and IgA antibodies were found in these patients' sera to whole seminal plasma of a normal male control and to fractionated proteins of different men, indicating that one or more homologous seminal plasma proteins may be responsible for these reactions. Their localized vaginal symptoms resolved completely after rapid immunotherapy treatment. Two of the women have remained symptom-free, whereas the third woman had recurrent localized vaginal symptoms after failing to maintain frequent sexual intercourse after treatment., Conclusions: Rapid immunotherapy immediately alleviated vaginal reactions to seminal plasma in all patients. These cases indicate that the pathogenesis of some localized vaginal inflammatory reactions may involve IgE-mediated or other immune responses to human seminal plasma proteins.

Background: Diisocyanate chemicals are leading causes of occupational asthma (OA)., Methods: We conducted a cross-sectional study of 243 workers exposed to diphenylmethane diisocyanate (MDI) in a urethane mold plant that had been designed to minimize MDI exposure (levels were maintained below 0.005 ppm and were continuously monitored). All participants were screened by questionnaire and tests for serum antibodies to MDI-human serum albumin (HSA). On the basis of questionnaire responses, diagnoses were derived that included OA; non-OA; work-related and non-work-related rhinitis; and lower respiratory irritant responses. Serial peak expiratory flow rate studies were performed for 2 weeks in 43 workers with and in 23 workers without lower respiratory symptoms., Results: Results of serial peak expiratory flow rate studies were abnormal in 3 (33%) of 9 workers with OA, in 2 (50%) of 4 with non-OA, and in 2 (9%) of 23 case control subjects. A significant association was found between peak flow rate variability and a questionnaire asthma diagnosis (chi 2 p < 0.002). Physicians confirmed three cases of OA, one of which occurred in a control worker who was free of symptoms. In all three cases asthma symptoms remitted after the worker left the workplace. Serum specific IgE and IgG levels were elevated in 2 of 243 workers, one of whom was prick test positive to MDI-HSA and had had cutaneous anaphylaxis after MDI exposure., Conclusions: On the basis of these cases, specific work activities associated with exposure to MDI were identified and corrective measures were instituted. Strict control and monitoring of ambient MDI exposure was associated with a low prevalence of specific sensitization to MDI and a lower than expected prevalence of OA.

A 26-year-old man employed in a company which manufactured hen egg white derived lysozyme for use in the pharmaceutical industry was evaluated for occupational asthma. The worker began to experience immediate-onset asthmatic symptoms two months after starting to work with egg lysozyme powder. The work process involved the production of approximately 1,000 kg of purified dried lysozyme powder per week. Prick skin testing was positive to egg lysozyme (50 mg/ml) and other egg protein components, but negative to whole egg white and egg yolk reagents. Serum specific IgE to egg lysozyme was documented. Decrements in serial peak expiratory flow rates were associated with lysozyme exposure at work. A specific bronchoprovocation challenge to lysozyme powder was positive demonstrating an isolated immediate asthmatic response (48 percent decrease from baseline FEV1). This is the first reported case of lysozyme-induced asthma specifically caused by inhalational exposure to egg lysozyme.

Acute sodium depletion in rats leads to dramatic increases in intake of hypertonic NaCl solutions, a behavior known as sodium appetite. The importance of signals conveyed by the chorda tympani (CT) nerve to the expression of sodium appetite is unclear. We examined the effects of bilateral CT transection on the short- and long-term response to sodium depletion in Wistar and Fischer 344 (F344) rat strains, because Wistar rats normally display a NaCl preference in the absence of need whereas F344 rats avoid NaCl. In both strains, sodium appetite after CT transection and treatment with the diuretic furosemide was delayed and blunted or eliminated. The results suggest that signals conveyed by the CT nerve are important in the expression of a sodium appetite. Effects on F344 rats are particularly interesting because CT transection surgery appears to have opposite effects on NaCl intake depending on whether F344 rats are sodium replete or deplete.

The present experiments examined whether behavioral conditioned responses (CRs) develop to LiCl-paired contextual and odor stimuli, and whether these CRs are similar to the behaviors observed following the administration of the drug. During conditioning, a novel context (Experiment 1) or a novel odor (Experiment 2) was paired with LiCl injections, and the CRs which developed to these stimuli were assessed during testing. Suppression of general activity occurred after LiCl exposure and after exposure to the lithium-paired context and odor. However, the actual behaviors which emerged as conditioned responses were distinctly different from those which were elicited by the drug itself. Lying on belly was the predominant unconditioned response to LiCl. Freezing was the predominant CR to the context, whereas gaping was the predominant CR to the odor. These outcomes are discussed and compared to previous results using a taste stimulus.

The density and species prevalence of dust mites were determined at various times over a 5-year-period in 252 homes of dust mite sensitive people with asthma who lived in eight geographic areas of the United States (Cincinnati, Ohio; New Orleans, La.; Memphis, Tenn.; Galveston, Texas; Greenville, N.C.; Delray Beach, Fla.; San Diego and Los Angeles, Calif.). The most common dust mites found in the homes were Dermatophagoides farinae (DF), D. pteronyssinus (DP), Euroglyphus maynei (EM), and Blomia tropicalis. All homes in all locations contained Dermatophagoides spp. mites, but few homes were populated exclusively by either DF or DP alone. Most homes (81.7%) were coinhabitated by both DF and DP. In coinhabited homes one species was predominant and usually made up at least 75% of the total mite population. Prevalence of the dominant or only species present varied between homes within a geographic area. EM occurred in significant numbers in 35.7% of homes in New Orleans, Memphis, Galveston, Delray Beach, and San Diego. Blomia tropicalis occurred in these same cities but in low densities. For all dust samples, only 13 homes of the 252 sampled had 100 or fewer mites/gm dust, which is considered to be the threshold for sensitivity. Most homes had average mite densities of 500 or more mites/gm dust. The results of the present study suggest a significant and widespread occurrence of both DF and DP. Therefore extracts of both mite species should be considered for diagnostic tests and immunotherapy. Significant levels of EM were present in some areas. Thus sensitivity to EM should be considered in these areas.

Peripheral gustatory mechanisms that may contribute to the expression of sodium (Na) appetite have been a focus of interest for many years. Because amiloride-sensitive Na transport is involved in the generation of neural signals in response to NaCl stimulation, the present study assessed whether changes in amiloride sensitivity of the neural response to NaCl accompany the induction of a Na appetite in the rat. Na deprivation was achieved by acute depletion with the diuretic furosemide. The magnitude of the whole-nerve chorda tympani response to 0.5 M NaCl was reduced in Na-depleted, compared with Na-replete, rats, which provides qualified support for previous reports that the induction of a Na appetite is associated with reduced neural responses to NaCl. However, changes in sensitivity to the specific Na channel blocker amiloride hydrochloride as a result of Na depletion were not evident. These findings suggest that the behavioral and neural changes that occur after Na depletion are not based on changes in amiloride sensitivity in the taste bud.

Pemirolast is a new oral, nonbronchodilator antiallergy medication that is being evaluated for the therapy of asthma. In this multicenter, double-blind, randomized study, 96 patients with mild asthma received pemirolast, 50 mg (n = 34); pemirolast, 25 mg (n = 31); or placebo (n = 31) BID for 6 weeks. Patients were evaluated weekly at the research centers; they maintained daily symptom diaries and measured peak expiratory flow rates twice a day. Methacholine challenge was performed at the start and end of the study. Results with pemirolast, 50 mg BID, showed statistically significant decrease in nocturnal symptoms (P = .02), in composite symptom scores (P = .02) and in bronchodilator use (P = .05) when compared with placebo. There were no statistically significant differences between treatments in pulmonary function tests or in methacholine challenge sensitivity. Pemirolast, 25 mg BID, did not differ from placebo. There were no significant adverse effects. Pemirolast, 50 mg BID, demonstrated sufficient antiasthma activity to warrant further studies in patients with more severe asthma and with higher doses.

A patient with severe acquired angioneurotic edema had essentially no C1- inhibitor activity in his serum and nearly died of cardiopulmonary arrest during an acute episode of facial, oral, and pharyngeal edema. This patient had an antibody directed against C1- inhibitor and C1- inhibitor-anti-C1- inhibitor complexes in his serum. The antibody required a normal residue (Arg) in the reactive center of the inhibitor for its optimal interaction with the inhibitor. Plasmapheresis with 5% human serum albumin replacement relieved him of his antibody load and the edema; additional treatment with pulsed cyclophosphamide has provided a sustained remission. The 5% albumin solution that was used contained functional C1- inhibitor; other lots that were tested contained only traces or none. No underlying disease has yet been identified. During this acute episode of edema, the C1- inhibitor in the patient's plasma was a 92 kd component, and on recovery, a 105 kd component reappeared. C1- inhibitor isolated from the patient's plasma, which was obtained before pheresis, was mainly in lower molecular weight forms (56 kd and 45 kd). The antibody in the patient's serum appeared to render C1- inhibitor susceptible to proteolysis, for when purified antibody was added to normal serum, a cleaved form of C1- inhibitor was generated.

The role of vasopressin (VP) in a sexually dimorphic behavior, the extinction of a conditioned taste aversion, was investigated in male and female rats of three different genotypes. This behavior was examined with a two bottle test in the wild-type Long-Evans (LE) rats, and then in partially VP deficient heterozygous (HET-BB) and completely VP deficient homozygous (HO-BB) Brattleboro rats. In Experiment 1, non-deprived male and female LE rats were given aversions to a sucrose solution by pairing it with a LiCl injection. The rate of extinction of the aversion upon reexposure to ad lib sucrose solution was examined and observed to be sexually dimorphic. Female LE rats extinguished at a significantly more rapid rate than males. Experiment 2 compared HET-BB and HO-BB male and female rats using the same paradigm. Neither of these VP-deficient groups showed sexual dimorphism of the extinction behavior. The data suggest that intact VP levels are necessary to observe the expression of this sexually dimorphic behavior.

The area postrema (AP), a chemoreceptor trigger zone for nausea and vomiting, has been implicated in taste aversion conditioning with LiCl. In addition to taste aversion acquisition, the present studies indicate that a number of other responses to LiCl administration are eliminated by lesions of the AP. These include a behavioral response, 'lying-on-belly' as well as two physiological responses, delayed stomach emptying and hypothermia. These findings suggest that the area postrema is critically involved in the detection of LiCl and in a wide range of responses to this toxin. They also provide strong evidence that the failure to acquire conditioned taste aversions to LiCl-paired flavors after AP lesions can be attributed to the absence of a significant 'illness' response in lesioned animals.

Single blind allergen (Ag) and saline solution bronchial challenges were performed on two successive study days in ten asthmatic subjects. Histamine challenges were performed before, at approximately 2 h (or after resolution of the immediate bronchial response [IR]), and 24 h after saline solution or Ag inhalation. Specific airway conductance (SGaw) was measured after delivery of challenge agents until a 50 percent fall in SGaw was observed. The SGaw was monitored over 8 h for immediate and late asthmatic responses (LAR). Results were expressed as provocative concentrations eliciting a 50 percent decrease in SGaw (SGawPC50HIS). No significant changes from baseline SGaw or SGawPC50HIS were demonstrated after saline solution. Eight subjects (dual reactors) exhibited both an IR and LAR after Ag and two had isolated IRs. Of the eight dual reactors, five had greater than 50 percent decreases in SGawPC50HIS immediately after resolution of the IR and six exhibited such decrements 24 h after Ag provocation. Mean baseline SGawPC50HIS (N = 10) on the Ag challenge day was 3.2 +/- 4.59 mg/ml and decreased to 0.92 +/- 4.56 mg/ml at 102 to 187 minutes after Ag (p = 0.0009) and was significantly decreased from baseline at 1.47 +/- 3.8 mg/ml 24 h after Ag (p = 0.0004). One of the two patients with isolated IR also showed an early onset increase in airway responsiveness (EOR). There was a significant correlation between the percentage of fall from baseline in SGawPC50HIS immediately after the IR and that at 24 h after Ag (r = 0.811, p = 0.005). There was no significant correlation between the decrease in SGawPC50HIS after the IR and the magnitude of the LAR. These data suggest that (1) the early events occurring prior to the LAR may determine changes in airway responsiveness observed at 24 h after Ag challenge, and (2) the EAR to histamine is not exclusively associated with the LAR.

We recently demonstrated morphine-6-hemisuccinate-human serum albumin conjugate (M-6-HS-HSA)-specific IgG in serum from ethic narcotics-manufacturing workers. In this article, we present results of epicutaneous tests to opiate compounds and lung-function studies in these same workers. Thirty-nine workers, exposed to opiates, were evaluated for possible work-related changes in lung function and were administered a questionnaire concerning opiate exposure and health history in February 1988. In December 1988, 33 employees with occupational exposure to opiates, six other workers (New Jersey referent) employed at the same factory with minimal exposure to opiate compounds, and 17 nonexposed individuals from Cincinnati, Ohio, were subjected to epicutaneous threshold testing with a panel of six opiate compounds and nine common aeroallergens. In opiate-exposed workers, significantly lower epicutaneous threshold concentrations were detected (compared to New Jersey referent and Cincinnati control subjects) for dihydrocodeine (p less than 0.01), hydrocodone (p less than 0.05), codeine (p less than 0.01), and morphine (p less than 0.05). Significant associates existed among epicutaneous threshold concentrations between the agents tested; that is, individuals with a positive morphine skin test would generally have a positive codeine skin test, etc. Atopic status (positive cutaneous test results to two or more of nine common aeroallergens) was not significantly associated (p greater than 0.05) with positive opiate skin sensitivity. Although the mean cross-shift decrements in FEV1 for all workers were nonsignificant, five opiate-exposed individuals demonstrated cross-shift decrements in FEV1 of greater than 10%. Daily maximum-minus-minimum changes in workweek PEFR (PEFRmax-min) were significantly reduced for Monday through Thursday (p less than 0.05) compared to PEFRmax-min changes during a nonwork, nonexposure 3-day weekend. Ten exposed workers demonstrated daily PEFRmax-min changes of greater than 20%, suggesting acute airway obstruction. Increased cutaneous reactivity to opiate compounds among opiate-exposed workers may reflect development of pharmacologic hyperresponsiveness to opiate compounds.

Fischer 344 (F-344) rats fail to prefer NaCl solutions to water at any concentration and avoid NaCl solutions preferred by other strains, including Wistar rats. Behavioral and electrophysiological responses of the mammalian gustatory system to NaCl have been shown to depend on a sodium transport system that is specifically blocked by lingual application of the sodium-transport blocker amiloride. The present study examined whether strain differences exist between F-344 and Wistar rats in the amiloride sensitivity of the chorda tympani (CT) electrophysiological response to NaCl. Whole nerve CT recordings were obtained from adult F-344 and Wistar rats during chemical stimulation of the anterior tongue. Responses to NaCl solutions ranging from 0.01 to 1.0 M were examined both before and after pretreatment with amiloride hydrochloride. Integrated whole nerve responses to NaCl solutions were expressed relative to the response to 0.5 M NH4Cl. Strain differences in the response to NaCl solutions emerged, with F-344 animals showing a significantly larger amplitude of the tonic response to NaCl, relative to NH4Cl, than Wistars. F-344 rats were also more sensitive to the sodium-channel blocker amiloride. These results suggest that strain differences in amiloride sensitive signals mediated by the CT nerve may contribute to the NaCl aversion displayed by F-344 rats.

Fischer 344 (F344) rats are atypical in their lack of preference for any concentration of NaCl solution over water. It was hypothesized that abnormal signals mediated by the chorda tympani nerve (CT) could be causally involved in NaCl avoidance by F344 rats. This study assessed whether CT transection would normalize the salt preference of F344 rats. Preference for NaCl solutions (0.6%, 0.8%, and 1.0%) versus water was assessed using two-bottle preference tests. At all concentrations tested, CT-transected animals preferred NaCl solutions to water. This preference differed dramatically from the avoidance of these solutions by controls. These findings are striking, particularly because CT transections have generally failed to significantly affect NaCl preference in other rat strains. The results are consistent with the hypothesis that in F344 rats the avoidance of the taste of NaCl stems from input mediated by the CT.